This application is an extension of our funded 2000 Trauma Center application and a resubmission of our competing renewal thaw was awarded bridge funding for 2004-2005. Our global hypothesis is that twoway exchanges between Human Core (housing clinical databases and patient samples) with mechanistic studies of inflammatory signaling will help us devise THERAPY FOR TRAUMA PRIMES CELLS. Since initial funding in 1993, our MOF databases have grown substantially to yield novel insights into fundamental problems inherent to hemorrhagic shock (I), transfusion (II), tissue injury (IV) and mechanisms of antiinflammatory resuscitation (V). The projects remain highly dependent on each other, and invite the Human Core to further test hypotheses. Proj. I focuses on cytotoxic properties of mesenteric lymph that occur after hemorrhagic shock, presumably due to mesenteric hypoperfusion. In this proposal we expand on the potential bioactivity of this lymph, the condition necessary for its toxicity, and attempt to dissect its components. Proj. II undertakes a detailed analysis of analogous lipid metabolites accruing in lymph and stored blood, focusing on lung endothelium. Proj. Ill focused on heat shock proteins but is being dropped form this proposal. Proj. IV focuses on another type of ubiquitous intracellular protein HMGBP that may be the penultimate effector of inflammation, caused by either cytokines or LPS. Curiously, its signaling mechanism could lead to the same LPS receptor pathway. Proj. V challenges other projects that signaling by inflammatory agents depends on large signaling complexes that form as activated receptors are internalized. Therefore, by disrupting assembly of the endosome-scaffolded signaling modules, inflammatory manifestations might be avoided. To validate these ideas, the Human Core is charged with supplying specimens, gather data, and re-annotate the database while remaining in strict regulatory compliance. With young clinicians and bio-statisticians returning to query this powerful database, we reassess the impact of changing therapy and develop new hypotheses for bench-testing in future cycles. A vigorous Cell &Imaging Core will provide each project with commonly used human cells, and equipment and expertise to perform advanced molecular colocalization and cytometry using antibodies. These efforts are supported by a seasoned Administrative Core that seeks to further the prowess of our three institutions to promulgate Trauma Research.